Elimination of Kalrn expression in POMC cells reduces anxiety-like behavior and contextual fear learning

Mandela, Prashant; Yan, Yan; LaRese, Taylor P.; Eipper, Betty A.; Mains, Richard E.

doi:10.1016/j.yhbeh.2014.07.001

Cited by 16 publications

(16 citation statements)

References 72 publications

(159 reference statements)

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“…Tissue and Cellular Specificity of PAM Ablation. As an initial determination of the sites of PAM depletion, Myh6-Cre and Emx1-Cre mice were individually crossed with TdTomato reporter mice, and Pam Emx1-cKO/cKO mice were studied directly (28). Direct observation of PAM at the cellular level was accomplished by immunocytochemistry as described (29) using affinity-purified PAM polyclonal antibody JH629.…”

Section: Methodsmentioning

confidence: 99%

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Identifying roles for peptidergic signaling in mice

Powers

Eipper

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Despite accumulating evidence demonstrating the essential roles played by neuropeptides, it has proven challenging to use this information to develop therapeutic strategies. Peptidergic signaling can involve juxtacrine, paracrine, endocrine, and neuronal signaling, making it difficult to define physiologically important pathways. One of the final steps in the biosynthesis of many neuropeptides requires a single enzyme, peptidylglycine α-amidating monooxygenase (PAM), and lack of amidation renders most of these peptides biologically inert. PAM, an ancient integral membrane enzyme that traverses the biosynthetic and endocytic pathways, also affects cytoskeletal organization and gene expression. While mice, zebrafish, and flies lacking Pam (PamKO/KO) are not viable, we reasoned that cell type-specific elimination of Pam expression would generate mice that could be screened for physiologically important and tissue-specific deficits. Conditional PamcKO/cKO mice, with loxP sites flanking the 2 exons deleted in the global PamKO/KO mouse, were indistinguishable from wild-type mice. Eliminating Pam expression in excitatory forebrain neurons reduced anxiety-like behavior, increased locomotor responsiveness to cocaine, and improved thermoregulation in the cold. A number of amidated peptides play essential roles in each of these behaviors. Although atrial natriuretic peptide (ANP) is not amidated, Pam expression in the atrium exceeds levels in any other tissue. Eliminating Pam expression in cardiomyocytes increased anxiety-like behavior and improved thermoregulation. Atrial and serum levels of ANP fell sharply in PAM myosin heavy chain 6 conditional knockout mice, and RNA sequencing analysis identified changes in gene expression in pathways related to cardiac function. Use of this screening platform should facilitate the development of therapeutic approaches targeted to peptidergic pathways.

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Section: Methodsmentioning

confidence: 99%

“…Mice were video recorded once for 5 min; times were obtained by watching the movies. Next, the general mobility and motor coordination of the mice were tested using the open field and rotarod (28,31). Rotarod testing was performed 3 times a day for 3 d using a Five Lane Rota-Rod for Mouse (Med Associates).…”

Section: Methodsmentioning

confidence: 99%

Identifying roles for peptidergic signaling in mice

Powers

Eipper

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…We had solid reasons to expect that the lines would be correct, given previous work on the specific DAT-Cre line we used [47] and the particular Drd1a-Cre and Drd2-Cre lines chosen [48], but a major impetus to do these tests was the unexpected occurrence with proopiomelanocortin (POMC)-Cre mice of the findings of Cre activity outside the population of cells that express POMC in the adult [43]. …”

Section: Resultsmentioning

confidence: 99%

Using Kalirin conditional knockout mice to distinguish its role in dopamine receptor mediated behaviors

et al. 2017

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BackgroundMice lacking Kalirin-7 (Kal7KO), a Rho GDP/GTP exchange factor, self-administer cocaine at a higher rate than wildtype mice, and show an exaggerated locomotor response to experimenter-administered cocaine. Kal7, which localizes to post-synaptic densities at glutamatergic synapses, interacts directly with the GluN2B subunit of the N-methyl-d-aspartate (NMDA; GluN) receptor. Consistent with these observations, Kal7 plays an essential role in NMDA receptor dependent long term potentiation and depression, and glutamatergic transmission plays a key role in the response to chronic cocaine. A number of genetic studies have implicated altered Kalirin expression in schizophrenia and other disorders such as Alzheimer’s Disease.ResultsA comparison of the effects of experimenter-administered cocaine on mice lacking all Kalirin isoforms to its effects on mice lacking only Kalirin-7 identified Kal7 as the key isoform whose deletion produces exaggerated locomotor responses to cocaine. Pretreatment of Kal7KO mice with a low dose of ifenprodil, a selective GluN2B antagonist, eliminated their enhanced locomotor response to cocaine, revealing an important role for GluN2B in this behavior. Selective knockout of Kalirin in dopamine transporter expressing neurons produced a transient enhancement of cocaine-induced locomotion, while knockout of Kalirin in Drd1a- or Drd2-dopamine receptor expressing neurons was without effect. As observed in Kalirin global knockout mice, eliminating Kalirin expression in Drd2-expressing neurons increased exploratory behavior in the elevated zero maze, an effect eliminated by pretreatment with ifenprodil.ConclusionsThe cocaine-sensitive neuronal pathways which are most sensitive to altered Kalirin function may be the pathways most dependent on GluN2B and Drd2.Electronic supplementary materialThe online version of this article (doi:10.1186/s12868-017-0363-2) contains supplementary material, which is available to authorized users.

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“…The 17 genes associated with anxiolytic-like effect on behavior, including that APOE [23], TSPO [24], UCP2 [25], MT1 [26], MT2 [27], AIM2 [28], CNR2 [29], LCN2 [30], DLK1 [31], CNTF [32], MYD88 [33], HDC [34], ALOX5 [35], TLR4 [36], ROCK1 [37], MOV10 [38], DDC [39]. The 9 genes associated with anxiety-like effect on behavior, including that LAMP5 [40], KALRN [41], CRHR1 [42], CCK [43], SNAP25 [44], OLFM2 [45], FAAH [46], IQSEC2 [47], EMX1 [48]. These data suggest that either the anxiolytic-like effects gene up-regulated or anxiety-like effects gene down-regulated could be a reduced level of anxiety.…”

Section: Multiple Gene Expression Changes Associated With Anxiety-relmentioning

confidence: 99%

Forebrain excitatory neuron-specific SENP2 knockout mouse displays hyperactivity, impaired learning and memory, and anxiolytic-like behavior

et al. 2020

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Sentrin/SUMO-specific protease 2 (SENP2) is a member of SENPs family involved in maturation of SUMO precursors and deSUMOylation of specific target, and is highly expressed in the central nervous system (CNS). Although SENP2 has been shown to modulate embryonic development, fatty acid metabolism, atherosclerosis and epilepsy, the function of SENP2 in the CNS remains poorly understood. To address the role of SENP2 in the CNS and its potential involvement in neuropathology, we generated SENP2 conditional knockout mice by crossing floxed SENP2 mice with CaMKIIα-Cre transgenic mice. Behavioral tests revealed that SENP2 ablation induced hyper-locomotor activity, anxiolytic-like behaviors, spatial working memory impairment and fear-associated learning defect. In line with these observations, our RNA sequencing (RNA-seq) data identified a variety of differential expression genes that are particularly enriched in locomotion, learning and memory related biologic process. Taken together, our results indicated that SENP2 plays a critical role in emotional and cognitive regulation. This SENP2 conditional knockout mice model may help reveal novel mechanisms that underlie a variety of neuropsychiatric disorders associated with anxiety and cognition.

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Elimination of Kalrn expression in POMC cells reduces anxiety-like behavior and contextual fear learning

Cited by 16 publications

References 72 publications

Identifying roles for peptidergic signaling in mice

Identifying roles for peptidergic signaling in mice

Using Kalirin conditional knockout mice to distinguish its role in dopamine receptor mediated behaviors

Forebrain excitatory neuron-specific SENP2 knockout mouse displays hyperactivity, impaired learning and memory, and anxiolytic-like behavior

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